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| Posted: 04 Jul 2008 04:05 PM CDT  Welcome to the latest edition of the Cancer Carnival: Your monthly carnival of news cancer care, treatment and latest research. Thanks to Ben for the logo design.First we start with a "blogging on peer review" post over at OMICS OMICS! In it, Dr. Robinson looks at a recent paper in nature which suggest a common target in multiple myeloma: IRF4. IRF4 is a transcription factor which regulates amongst other things the powerful oncogene MYC and has been known to be translocated in some myelomas. The author notes: "An interesting further bit of work targeted various identified IRF4 targets and showed these knockdowns to be lethal to myeloma cell lines. Hence it is suggested that IRF4 ablation in myeloma would lead to tumor cell death by many routes. Mice heterozygous for IRF4 deletion are viable, suggesting that IRF4 could be targeted safely." While this is an exiting new finding in the field, Dr Robinson astutely points out that transcription factors are generally poor therapeutic targets... Our next story comes from Cancer and Your Genes and examines how genomics can predict prostate cancer survival. As tools become more readily available and cheaper, the dream of personalised medicine is to use personal gene profile and compare it against large epidemiological databases to extract useful information for treatment. The paper discussed by Dr. Mealiffe appeared in the Journal of Clinical Oncology and paves the way by looking at 600 father-son pairs afflicted with prostate cancer: "they were able to show that sons of fathers with shorter survival from prostate cancer tended to survive for a shorter period as well. Likewise, sons of fathers who survived for a longer period of time after the diagnosis tended to survive for a longer period of time as well." Next we learn about neurofibromatosis, a type of famillial cancer which affects nervous tissues, often in young patients. Highlight in Health discusses some of the mutations underlying the disease in the NF1 and NF2 tumour suppressors and other topics covered at a recent conference in Florida. "The conference was attended by over 200 researchers from around the world This year's theme — Genes to Complications to Treatments — highlighted the progress being made in NF research and clinical care, as well as the research programs of the Children's Tumor Foundation. Last year's NF Conference focused on models, mechanisms and therapeutic targets. "  A great blog post on peer-reviewed research over at Hematopoiesis explains what systemic instigation is, and what are the roles of hematopoietic stem cells, and osteopontin in this process:"To summarize - some tumors can do kind of magic (on systemic level, - through release some factors into the blood) with bone marrow, progenitor populations in particular; this magic is called "instigation"; functionally perturbed bone marrow cells leave their niches and are mobilized into stroma of tumor-responder, that causes its growth and metastases."  Rob also wants to plug his paper which has to do with engineering viruses to kill cancer cells or something like that. Congratulations Rob, I guess we should develop an icon for blogging on self-reviewed research :"Oncolytic viruses are replicating viruses that replicate in tumour cells while sparing normal cells. Preclinical and early clinical data demonstrates great promise for this class of cancer therapeutic. A recent paper has demonstrated that vesicular stomatitis virus can be targeted to tumour cells that show low expression of the microRNA let-7. Low let-7 expression is associated with many cancers, possibly because it is involved in the inhibition of expression of a few oncogenes. A VSV designed to be inhibited by let-7 demonstrates attenuated replication in normal cells but not in low let-7 expressing cancer cells. The authors suggest that this has broad applications in the field and could be used in order to enhance the potency of some other oncolytic viruses." Also I want to point out 3 interesting posts from ScienceBorgs, which were not submitted to the carnival but warrant your attention. Mike the Mad Biologist talks about how the HTLV-1 virus can protect against certain forms of cancer, Terra Sigillata discusses the funding environment for cancer research, and Pharyngula chymes in with a plea for more funding with a personal story.  Well our carnival wouldn't be complete without the quack submissions. In this case I wouldn't really call it quack because the authors are well meaning and talk about valid science but sometimes come up to the wrong conlusions. Danny talks about IP6, a nutritional suplement and about some of the preliminary work that suggests some activity in cancer. Dan was approached to carry an add about IP6 on his blog and decided to look further into it. A good skeptical blogger. The add stated that:"A revolutionary dietary supplement that address many of the causes of the aging process and have been scientifically proven to support natural cell defence producing outstanding results in improving the health of patients with cancer and diabetes, lowering the risk of kidney stones and heart disease, and helping to ease many other health concerns." While Dan finds some supporting evidence he agrees that the claims are largely exaggerated. He also correctly points out that you can't generalise from rodent models to humans. He however indicates that he would gladely take the stuff if he had cancer. Just a note of precaution, many of the these supposedly "natural" or "safe" supplement may be perfectly fine in healthy individuals but can interfere adversly with treatment. Always consult your physician and be warry of lofty claims about supplements. More concerning is this post from Cheryl. It is so full of innacuracies, I don't know where to start. Again it starts with real science but then becomes distorted. Let me correct at least some of them. 1-It's true sugar or glucose does feed cancer cells, it also feeds all the other cells in your body. Your brain exclusively functions on that stuff. Limiting consumption is not an effective way to fight cancer per se, but it may be good for your health overall, as long as it's within reason. However you might want to read our previous posts about the Warburg effect to see exactly how difference in metabolism can be exploited therapeutically in a more effective way. 2-I'm not sure how you got the idea that milk produces mucus and that cancer cells eat mucus. Some studies have suggested weak links between cow milk and cancer rates, however it has nothing to do with mucus. 3-Tumours sometimes grow in an hypoxic and acidic environment (see warburg effect from above). However eating meat does not make you more acidic and create a good environment for cancer. Red meat by definition is exactly as acid as you are. Fruits and vegetables on the other hand can sometimes be very acidic, but no need to worry, They wont change the overall pH of your body. 4-Do not avoid coffee, tea and chocolate! They are full of cancer-fighting compounds, and they taste good. Just read up on flavonoids, anti-oxidants etc... Caffeine is not a significant epidemiological risk for the vast majority of cancers, and any association is generally extremely weak. That concludes the 11th edition of the Cancer Research Blog Carnival. If you'd like to host in the future, send an email to bayblab[at]gmail.com and submit posts to future editions here. |
| Gecko genome size and cell size. [T Ryan Gregory's column] Posted: 04 Jul 2008 12:12 PM CDT One of the many aggravations I encounter when reviewing manuscripts is that some authors greatly overstate the applicability of statistically significant patterns they report. |
| Freedom from Hunger- science can lend a helping hand [Tomorrow's Table] Posted: 04 Jul 2008 12:00 PM CDT Each year an estimated 15 million hectares of rice lands (a region half the size of Italy) in South and Southeast Asia are inundated by flash floods. In Bangladesh, during the monsoon, roads are so wet that they become waterways for homemade sailboats rigged with cloth, jute, and bamboo. Such lands are home to an estimated 140 million people of whom 70 million are living on less than $1 a day, the highest concentration of poor people in the world. Here, losses of rice production can be over $1 billion per year. This number, however does not capture the human suffering caused by the catastrophic crop losses where people get about two-thirds of their total calories from rice. Although rice is the only cereal that can withstand some flooding, most rice varieties will die if submerged for too long. There are a few rare exception and these are of great interest to rice breeders. One of these is the traditional Indian rice variety, FR13A. This rice plant has an unusual and agronomically important trait- the seedlings are able to withstand fourteen days of submergence. It is, however, low yielding and no longer widely grown. FR13A originated in the state of Orissa, in eastern India, bordered on the east by the Bay of Bengal. Hindu temples dating to the thirteenth century are scattered through the area. Today most of the people there still speak the ancient dialect of Oriya, and the majority are still rice farmers. For over fifty years, breeders tried to use FR13A as a parent plant to introduce the submergence tolerance trait into high yielding, tastier varieties favored by rice farmers in other parts of Asia. Frustratingly, the resulting new varieties were of poor quality. The main reason for thisbreeding failure was that, because they were not really sure which genes were needed or where in the genome they were located, the breeders accidentally introduced other genes that reduced the overall quality of the rice. In 1996, Dave Mackill, a scientist at the International Rice Research Institute who had been studying this problem for 10 years, asked if I would use my expertise in rice genetics to help him identify the submergence tolerance gene from FR13A. Within a couple of years after joining my lab, the husband and wife team of Kenong and Xia Xu were able to locate the submergence tolerance trait to a very small region of one of the rice chromosomes. Computer programs allowed us to predict the function of the genes in this region, one of them, an ethylene responsive transcription factors, was of particular interest. Based on what we knew about this gene, we hypothesized that it might act as a master switch to regulate complex functions of the plant. It was as if Kenong and Xia had been able to unravel a ball, woven from 42,000 silken threads all of a slightly different hue, and to pull out one thread, interlaced but distinct from the others. Unlike weavers, geneticists cannot determine if the thread they hold is the one they want simply by looking at it; instead they need to test it by weaving it into another pattern—in this case another rice plant that normally cannot survive floods. So that is what we did. We genetically engineered (GE) this single thread, carrying the submergence tolerance trait, into a rice variety that normally would die in a flood. We wanted to know if incorporation of this one gene would allow the plant to survive. To test this hypothesis, we transplanted the young GE seedlings and then submerged them for over two weeks. After 10 days, we could see that only a few of the control rice plants lacking the gene survived the flood and these were weak, spindly and very pale. The flaccid appearance is typical of plants that have drowned, lacking the air and sun- light needed to function. It was unlikely that this group of plants would survive much longer. We then looked at the row of GE plants that carried the genetic information from the submergence tolerant Indian variety. If we had identified and introduced the correct gene, the plants would have survived the extended time underwater and recovered. I hurried over and gently touched the bright green leaves of the first plant. My eyes quickly traveled down the row. They were alive. It was as though the rice plants had been able to hold their breath until the water was gone. Our work represents the latest genetic change in the rice plant, which was first cultivated along the Yangtze River 6000 years ago. Since that time, hundreds of thousands of rice varieties have been developed. It is likely that FR13A was selected by Orissan farmers because it could survive the floods particular to that area. It was then handed down from one generation to the next, prized then, as now, for its submergence tolerance. We now know that the submergence tolerance trait is found not only in the Orissan variety, but also in two traditional varieties from Sri Lanka. It appears that ancestors of the Sinhalese, who originated from Orissa and migrated to the island twenty-five hundred years ago, transported these precious rice grains over thousands of kilometers. Perhaps as geneticists, we are acting as humans have always done: learning the secrets of the sacred and ancient and passing that knowledge to others, who will then use that information in a new and unexpected way. The submergence tolerance gene has now returned to southern Asia in another new form. With the use of marker-assisted breeding (a kind of hybrid between conventional breeding and genetic engineering) Dave and coworkers have introduced this gene into rice varieties that are adapted to habitats in South and Southeast Asia. These genetically modified plants can withstand fourteen days of submergence, and they yield and taste the same as their parent variety that is popular with local growers. Last fall Dave assessed the productivity of these varieties on farm trials in Bangladesh. The weather in Asia last year was ferocious. Monsoon rains inundated countries from the Philippines to Nepal. Super typhoons slammed into China and Japan. All of this was bad for rice. And what's bad for rice is especially bad for Bangladesh. Jon Hamilton, a National Public Radio correspondent, recently interviewed farmers who had planted sub1 rice. This is his report: "Gobindra Chandra Rai is a farmer whose field had been under water just a few weeks earlier. He says that when the floods came, the whole area was submerged up to about waist high. The government gave farmers in Gobindra's village seedlings with the flood-resistance gene, but most hadn't planted them in time. When the monsoon floods came early, Gobindra was the only one that had. So he and his neighbors watched Gobindra's field anxiously. The field was under water for eight days. Gobindra says that usually after eight days, the crop would be damaged. But the sub-1 rice is still thriving. He tends to it carefully. If a stalk is leaning, he straightens it. If a leaf is muddy, he squeezes it clean between two wet fingers. Gobindra says his neighbors are amazed by what they've seen in his paddy. Standing in a semi-circle in front of a shed made of bamboo and corrugated sheet metal, they line up to talk about Gobindra's rice. Men stand up front. Women farther back. And little boys climb on anything tall enough to give them a better look. Many of the farmers can't read or write. But when it comes to rice science, they're at the cutting edge. And every single one in Gobindra's village now plans on planting the sub-1 variety." Xu, K., Xu, X., Fukao, T., Canlas, P., Maghirang-Rodriguez, R., Heuer, S., Ismail, A.M., Bailey-Serres, J., Ronald, P.C., Mackill, D.J. (2006). Sub1A is an ethylene-response-factor-like gene that confers submergence tolerance to rice. Nature, 442(7103), 705-708. DOI: 10.1038/nature04920  |
| Posted: 04 Jul 2008 10:23 AM CDT ScienceDebate2008 has come up with 14 questions they would like to see answered by the US presidential candidates. This group has been pushing for a science policy-focused debate among presidential candidates. That debate is looking more and more unlikely, but in an effort to keep some of the election focus on science, this group is now urging the candidates to answer a set of questions on science policy (abbreviated below - go read the questions in full at the ScienceDebate2008 site): 1. What policies will you support to ensure that America remains the world leader in innovation? 2. What is your position on the following measures that have been proposed to address global climate change—a cap-and-trade system, a carbon tax, increased fuel-economy standards, or research? 3. What policies would you support to meet demand for energy while ensuring an economically and environmentally sustainable future? 4. What role do you think the federal government should play in preparing K-12 students for the science and technology driven 21st Century? 5. What is your view of how science and technology can best be used to ensure national security and where should we put our focus? 6. In an era of constant and rapid international travel, what steps should the United States take to protect our population from global pandemics or deliberate biological attacks? |
| My First Impact Factors [ScienceRoll] Posted: 04 Jul 2008 08:26 AM CDT I know it’s a small step for a scientist but an exceptional day for me as I’ve got my first impact factors (2.78!).
I hope to get some more, next time in the field of genetics. I had another publication about web 2.0 and medicine but this one was published in Hungarian. Anyway, according to Wikipedia, impact factor is a measure of the citations to science and social science. journals.         |
| Posted: 04 Jul 2008 07:56 AM CDT Now, you know we have Pubmedfight in our hands to be able to resolve disputes between two scientists. But what about InterMEDI, a collaborative intelligence for biomed professionals. Excerpts from the blog Personomics:
And if you would like to use a search engine that is quite different from Pubmed, check Scienceroll Search out and let us know your opinion.         |
| Around the Blogs [Bitesize Bio] Posted: 04 Jul 2008 05:24 AM CDT Some interesting and thought-provoking posts from “Around the Blogs.” Some are weeks-old… sorry ’bout that, but that’s what happens when you take a couple weeks off. Check ‘em out, starting with: Graduate School and Teaching, AKA ‘Why Grad Students Should Teach,’ by guest Joel Corbo at Cosmic Variance. The post was written with physics students in mind, but applies equally well to biologists. Cell Potpourri: Eukaryotes and their Organelles, with comments on new peer-reviewed papers (Open Access) at Twisted Bacteria. Structure of an R01: Specific Aims - Suggestions and more from PhysioProf at Drug Monkey. Only Nature Could Turn the Success of PLoS ONE into a model of failure - Jonathan of Tree of Life tears down a rather inept editorial published in Nature. |
| The Singing Cavemen [HENRY » genetics] Posted: 04 Jul 2008 01:42 AM CDT ….and the award for the stupidest science story I’ve seen in months goes to LiveScience.com for “Cave Men Loved to Sing“, in which we’re told that our cave-dwelling ancestors used echo-location:
This work is good, because… “(some work was done in past years and combined with the latest findings)”. A scientific paper being based off previous findings… Fancy that. The conclusions? -
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| Taste Sensation [Sciencebase Science Blog] Posted: 04 Jul 2008 01:25 AM CDT
Well, the small amount of salt (sodium chloride) added to food has very, very little effect on the boiling point and so really does not affect how quickly the food cooks. The fundamental reason we like to cook with salt is that salt has not only its own taste, but also interferes with the bitter-taste receptors on the tongue, essentially blocking them temporarily and so masking the taste of any bitter compounds in the food you eat, therefore emphasising any sweet tastes. It really is purely there as a flavour enhancer. Try it with some raw lettuce, eat a leaf raw and concentrate on the bitterness. Then sprinkle on some salt and eat the second leaf, besides the taste of the salt, you will notice it actually tastes sweeter. Given how bitter and downright nasty some vegetables can taste raw - think Brussels sprouts, spring cabbage, turnip - and perhaps more so in days gone by when quality may have been even lower, it is easy to see why adding salt to the cooking pot would have become standard practice. This was covered in New Scientist a while back. The sodium salt of the glutamic acid, commonly known as MSG (monosodium glutamate) does even more, it has the bitter-blocking sodium ionsbitter-blocking sodium ions. It adds a frissant through the stimulating “deliciousness” (umami, in Japanese, from the word for savoury) of the glutamate. Some research indicates that there are umami receptors on the tongue representing a fifth taste sensation alongside bitter, sweet, salt, and sour. Different research again adds a sixth taste sensation to our tongues, claiming a receptor for fatty acids. Given the highly stimulating effects of salt (as taste and bitter blocker), MSG, and fat (in the form of fatty acids) on our tongues it is perhaps no surprise then that salt-laden fatty foods taste so delicious. A post from David Bradley Science Writer |
| New antibiotic beats superbugs at their own game [Think Gene] Posted: 04 Jul 2008 12:20 AM CDT
The research, to be published in the August 2008 issue of the journal Antimicrobial Agents and Chemotherapy and available online now, looked at how well Ceftobiprole worked against bacterial clones that had already developed resistance to other drugs. In every case, Ceftobiprole won. “It just knocked out the cells 100 percent,” says the study’s lead investigator, Alexander Tomasz, head of the Laboratory of Microbiology at Rockefeller. Previous research had already shown that — in general — Ceftobiprole was highly effective against most clinical isolates of S. aureus. “Instead, we looked more carefully at the highly resistant cells that already occur in such clinical isolates at very low frequency — maybe in one bacterium in every 1,000,” says Tomasz. Ceftobiprole was able to kill these resistant cells. Never before has an antibiotic been tested this way. “In the history of antibiotic development, an antibiotic arrives on the scene, and sooner or later resistant bacteria emerge,” Tomasz says. “We sought to test in advance which would win this particular chess game: the new drug, or the bacteria that now cause human deaths.” In an ominous new “move” in this chess game, S. aureus strains with resistance to vancomycin (VRSA), a different class of antibiotics, also began to appear in hospitals in the United States. Ceftobiprole was also able to kill these new resistant VRSA strains. The drug is effective because the chemists who developed Ceftobiprole managed to outwit the bacteria at their own game, Tomasz says. The broad-spectrum antibiotic was discovered by Basilea Pharmaceuticals, based in Basel, Switzerland, and is being developed in the U.S. and worldwide by Johnson & Johnson. The research was supported by Johnson & Johnson along with a grant from the U.S. Public Health Service. Source: Rockefeller University Josh: This new antibiotic appears to be a modified β-lactam ring. β-lactams are present in a broad range of antibiotics, but many bacteria are developing a resistance to them, such as MRSA. |
| Myeloma unified? [Omics! Omics!] Posted: 03 Jul 2008 09:46 PM CDT  Multiple myeloma is a complex disease. Perhaps one metaphor is that of the mythical Hydra -- each time a new molecular tool is thrown at it the number of vicious heads increases. For example, there are different chromosomal translocations which lead to myeloma. If you look at myeloma samples by transcriptional profiling, then one can find distinct expression signatures for each translocation -- and just as easily find ways to split those signatures into further subtypes. For example, some translocations activate one gene disrupted by the translocation whereas other instances of the same translocation will activate both deranged genes. Another possible metaphor is the old fable of blind men examining an elephant -- each reports that the object is different, based on examining a different portion of the beast. In the case of myeloma, one examiner might focus on the subset with large portions of the genome amplified, others on specific deletions on chromosome 13, another on those cases where bone destruction is rampant. My own experience with palpitating the pachyderm looked at the response to a specific drug. Now the Staudt lab has come out with a paper in Nature which proposes lumping everything back together again. Initially using a retroviral RNAi screen they identified the transcription factor IRF4 as a unifying theme of myeloma. IRF4 is activated in one characteristic translocation and plays an important role in B-cell development, so it's not a total shock. But linking it across multiple types is surprising. The screen achieved 2-8 fold knockdown of IRF4 in 3 different myeloma cell lines, each possessing a different hallmark translocation (one of which was an IRF4 translocation). This was later extended to additional myeloma lines with similar lethality, but the knockdown of IRF4 in lymphoma lines had little effect, save one line possessing a translocation of IRF4. One interesting surprise is that with the exception of the known IRF4 translocation bearing line, none of the lines have amplifications or other obvious derangements of IRF4. Only one showed point mutations upon resequencing. Hence, somehow IRF4 is being activated but not via a painfully obvious mechanism. RNAi approaches can suffer from off-targets, genes not meant to be hit which cause the phenotype being studied rather than the believed target. The paper provides strong evidence that the effects really are driven by IRF4 knockdown -- not only were multiple shRNAs targeting IRF4 found to kill myeloma cells, but one of these targets the 3' untranslated region of IRF4 -- and the phenotype could be rescued by expressing IRF4 lacking the 3' UTR. Transcriptional profiling of the knockdown lines in comparison with parental lines revealed a number of candidate IRF4 targets, and a large number of these were also identified by chromatin immunoprecipitation-chip (ChIP-chip) studies, confirming them as direct IRF4 targets. As noted, some direct targets may have been missed by ChIP-chip due to limitations with the arrays used. One other interesting aspect: the IRF4 target list in myeloma lines somewhat resembles a union of that in plasma cells (the normal cell myelomas are most kin to) with that of antigen-stimulated B-cells. A particularly interesting direct IRF4 target identified in this study is the notorious oncogene MYC. A number of identified IRF4 targets are also known MYC targets, suggesting synergistic activation. They also found that both IRF4 and MYC bind upstream of IRF4 -- suggesting a complex web of positive feedback loops. An interesting further bit of work targeted various identified IRF4 targets and showed these knockdowns to be lethal to myeloma cell lines. Hence it is suggested that IRF4 ablation in myeloma would lead to tumor cell death by many routes. Mice heterozygous for IRF4 deletion are viable, suggesting that IRF4 could be targeted safely. The catch would be targeting IRF4 -- transcription factors are on nobody's list of favorite targets. The authors cite as points of optimism approaches targeting p53 & BCL6. However, the p53 targeting route is by inhibiting an enzyme which destabilizes p53, so an analogous approach to IRF4 would require first identifying key determinants of its stability. The BCL6 example they cite uses a peptide mimic, not something the medicinal chemists love much. Other approaches to targeting IRF4 might focus on "druggable" (if any) genes in the IRF4 target lists, or perhaps something else. I'll try to put together a post next week on one of those candidate elses. Now that Staudt's group has brought things together, it is tempting to contemplate slicing off some more Hydra heads. How do IRF4 target gene profiles differ across the chromosomal abberation subtypes of myleoma? Do IRF4 targets have any predictive value for determining the appropriate medication or show differential response to different medications? |
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